Capsicum consists of the dried ripe fruits of Capsicum annuum Roxb. (Family Solanaceae), a small erect shrub indigenous to tropical America, cultivated in South America, China, India and Africa. Capsicum contains a crystalline pungent principle capsaicin, traces of a liquid alkaloid, red coloring matter and a fatty oil. In folk medicine, capsicum is regarded as an aphrodisiac, depurative, digestive, stomachic, carminative, antispasmodic, diaphoretic, antiseptic, counterirritant, rubefacient, stypic, and tonic. Internally, capsicum has been used to treat asthma, pneumonia, diarrhea, cramps, colic, toothache, flatulent dyspepsia without inflammation; insufficiency of peripheral circulation; as a gargle for sore throat, chronic pharyngitis and laryngitis; and externally as a lotion or ointment to treat neuralgia, including rheumatic and arthritic pain, and unbroken chilblains (cold injuries) (Duke, 1985; Leung and Foster, 1996; Newall et al., 1996).
In Germany, cayenne pepper is official in the German Pharmacopeia and approved in the Commission E monographs as a topical ointment for the relief of painful muscle spasms in the upper torso (DAB, 1997). In the United States, capsicum tincture and oleoresin were formerly official in the United States Pharmacopeia and National Formulary. Capsicum USP was used as a carminative, stimulant, and rubefacient (Leung and Foster, 1996; Taber, 1962).
The most potent and predominant chemical entity in capsicum is capsaicin (0.14%) (Cordell and Araujo, 1993; FIG. 1). The heat sensation of pure capsaicin is approximately 16 million Scoville heat units (SHU) and is so hot that in its pure form diluted one hundred thousand fold it can cause blistering of the tongue. A series of homologous branched- and straight-chain alkyl vanillylamides, collectively known as capsaicinoids, is present in lesser concentrations than the parent compound, capsaicin. Of the capsaicinoid fraction, capsaicin (48.6%) is quantitatively followed by 6,7-dihydrocapsaicin (36%), nordihydrocapsaicin (7.4%), homodihydrocapsaicin (2%), and homocapsaicin (2%) (Duke, 1985). Capsaicinoids and capsaicin are collectively found in amounts of 0.1% to 1%, with quantities varying according to soil and climate (Rumsfield and West, 1991).
Capsaicin, a colorless crystalline substance, was first synthesized in 1930. Capsaicin has been studied since the mid-19th century and its structure is elucidated as 8-methyl-6-nonenoyl vanillylamide (Cordell and Araujo, 1993). Most pharmacological studies performed with isolated constituents of chile pepper have focused on capsaicin, which is the major pungent constituent.
The crude extract of capsicum fruits, known as capsicum oleoresin, contains at least 100 different volatile chemical constituents, and therefore may function in differing ways from pure capsaicin. Thus, it is important to distinguish between studies using capsaicin and those employing capsicum oleoresin (Cordell and Araujo, 1993).
Nonivamide (pelargonic acid vanillylamide) is a common synthetic adulterant of capsicum products. Although structurally different from capsaicin, its presence in capsicum or capsaicin samples can be detected spectrographically and there is no evidence that this compound occurs naturally in Capsicum (Cordell and Araujo, 1993).
Capsaicin affects lipid metabolism as demonstrated in a study by Kawada et al. (1986). Male rats fed a diet containing 30% lard with capsaicin at 0.14% of the diet developed serum triglyceride levels that were significantly lower than those of animals receiving a high-fat diet without capsaicin. But levels of free fatty acids, cholesterol, and pre-beta-lipoprotein were not affected. Activities of liver enzymes involved in lipid synthesis (acetyl-CoA carboxylase) and in carbohydrate metabolism (glucose-6-phosphate dehydrogenase) were inhibited in the high-fat diet, but the activity of the latter was restored to control levels by the added dietary capsaicin. The weight of perirenal adipose tissue was reduced in a dose-dependent manner by capsaicin. These results suggested that capsaicin did not interfere with lipid biosynthesis. Rather, that capsaicin might stimulate lipid metabolism, and possibly facilitates mobilization of lipid from adipose tissue.
In a follow-up to the study above, Kawada et al. (1986a) measured the effect of i.p. administered capsaicin on general energy metabolism, including oxygen consumption, respiratory quotient, and substrate utilization. Capsaicin had a general stimulatory effect on metabolism, similar to that of epinephrine; oxygen consumption was elevated, respiratory quotient was initially elevated, then decreased; and serum glucose and insulin levels were elevated, concomitant with a rapid decrease in liver glycogen, and a gradual increase in serum triglycerides. The response was blocked by beta-adrenergic blockers, but was not effected by alpha-adrenergic or ganglion blockers. Their results suggested that capsaicin effects metabolism either as a direct beta-adrenergic agonist, or indirectly by stimulating catecholamine release.
Yamato et al. (1996) showed that capsaicin produced a marked concentration-dependent decrease in the amplitude, the rate of rise, and the rate of relaxation of the contractile tension of rat ventricular papillary muscles; however, the half-life of the relaxation and the time to peak tension were only slightly effected. Calcium release and shortening of action potential duration in ventricular myocytes was profoundly reduced by capsaicin, perhaps resulting from the non-specific membrane-stabilizing effects of capsaicin.
Capsaicin treatment caused a biphasic effect on contractile force, left ventricular systolic blood pressure, and heart rate of isolated perfused rat hearts. A transient initial increase in contractile force and left ventricular systolic pressure was observed, followed by a prolonged depression of both parameters. Heart rate was increased, but this effect was not followed by a subsequent reduction. The initial increases in contractile force and blood pressure could have been induced by the release of calcitonin-gene-related peptide (CGRP) from local sensory nerves; the negative inotropic effects following the initial increase may be due to a direct inhibitory effect of capsaicin on ventricular cells, or to nonspecific membrane-stabilizing effects. The increased heart rate was attributed to the release of CGRP (Lundberg 1985).
Capsaicin elicits a vasoconstrictive response in the large cerebral arteries of the cat (Saito et al., 1988), and in the middle and basilar cerebral arteries, an effect was attributed to a direct contraction of smooth muscle, since the response was independent of the presence of endothelium and nerve components. However, Saito et al. found results suggesting that while capsaicin releases and depletes vasodilator peptides from perivascular nerves, the direct vasoconstrictor effects of capsaicin overwhelm the vasodilator effects of these peptides.
An increased activity of CGRP-containing trigeminovascular nerve fibres has been correlated to the pathophysiology of migraine (Buzzi et al., 1991) either during attacks (Goadsby et al., 1990; Goadsby & Edvinsson, 1993) or as ageneral imbalance in migraine patients (Ashina et al., 2000). Therefore, clinical potentials of CGRP receptor antagonists in the treatment of migraine have been addressed (Doods et al., 2000). Capsaicin (Holzer, 1991b; Szallasi & Blumberg, 1999) potently and selectively causes release of CORP from sensory nerve terminals both in vitro and in vivo (Duckles & Levitt, 1984; Duckles, 1986; Holzer, 1991a; Saito & Goto, 1986; Wharton et al., 1986). The mechanism of capsaicin-induced CGRP depletion involves binding of capsaicin to vanilloid 1 receptors (VR1) (Caterina et al., 1997). Capsaicin-association to VRs triggers Ca2+ influx and elevated intracellular calcium levels in turn stimulate CGRP-release. The vanilloid 1 receptor is in addition to capsaicin stimulated by heat, hydrogen ions, lactate (Franco-Cereceda & Liska, 2000; Franco-Cereceda, 1988) and the endogeneous cannabinoid, anandamide (Zygmunt et al., 1999).
A hypoxic reflectory release of CGRP which has been suggested in myocardium (Kallner, 1998; Dai et al., 2000; Franco-Cereceda & Liska, 2000) and in cerebral arteries (McCulloch et al., 1986) may be due to stimulation of this receptor as well. It has previously been demonstrated that CGRP, rather than SP and NKA, is responsible for the capsaicin-induced vasodilatation of guinea-pig basilar artery (Franco-Cereceda & Rudehill, 1989; O'Shaughnessy et al., 1993; Jansen-Olesen et al., 1996).
In tests using cultured human intestinal epithelial cells, Jensen-Jarolim et al. (1998) found sufficient in vitro evidence to suggest that Capsicum may increase the permeability of the gastrointestinal tract to allow transport of macromolecules and ions across the epithelium; an effect, they add, that might have importance to food intolerance and allergic reactions to food. The stimulatory effect of orally administered capsaicin on gastric acid secretion and mucosal blood flow was studied in rats using amounts roughly equivalent to a normal Thai diet. Capsaicin was noted to have a protective effect on gastric mucosa of ethanol-induced gastric lesions in rats (Uchida et al., 1991). The protective effect was attenuated upon pretreatment with indomethacin and disappeared in capsaicin-sensitive nerve-degenerated rats, suggesting that enhanced prostaglandin formation inhibited lesion formation. Further study by the same group found decreased stomach motility and increased mucosal blood flow with intragastric capsaicin treatment, whereas capsaicin pre-treatment desensitized the afferent neurons, thereby mitigating this protective effect.
An in vitro chemopreventive activity of capsaicin was shown by Morr et al. (1995). When capsaicin was added to cultured cells of Caov-3 human ovarian carcinoma, MCF-10A human mammary adenocarcinoma, HL-60 human promyelocytic leukemia, and HeLa cells, a preferential growth-inhibition was evident as cells became smaller and underwent cell death. Condensed and appearing fragmented, the nuclear DNA of these cells suggested that capsaicin had induced apoptosis.
The arachidonic acid cascade is an important component of inflammation and the associated localized immune response. The release of arachidonic acid (AA) from membrane phospholipids and subsequent leukotriene biosynthesis occurs during inflammation, and products formed by AA oxidation act in concert with numerous other factors, including cytokines, PAF (platelet-activating factor), nitrogen oxide, and histamine, all of which are important mediators of the immune response. A study (Panossian et al., 1996) found that at low concentrations capsaicin stimulated the production of interleukin-1a, while at higher doses it inhibited this response. Capsaicin caused a dose-dependent release of AA from PMNs (poly-morphonuclear leukocytes), and a similar concentration-dependent conversion of the AA metabolites, prostaglandin E2 (PGE2) and LTB4. When incubated with granulocytes, capsaicin caused an increased synthesis of 12-HETE, an eicosanoid metabolite of AA, but at the same time was found to cause a dose-dependent decrease of all products of 5-lipoxygenase. These results suggested that the dose-dependent reversible effects of capsaicin on immune cells and interleukin-1alpha are closely associated with arachidonic acid metabolism (Panossian et al., 1996).
Viral replication, immune regulation, and induction of various inflammatory and growth-regulatory genes require activation of a nuclear transcription factor (NF)-κ-B. Agents that can block NF-κ-B activation have potential to block downstream responses mediated through this transcription factor. Capsaicin (8-methyl-N-vanillyl-6-nonenamide) has been shown to regulate a wide variety of activities that require NF-κ-B activation (Singh 1996). The pretreatment of human myeloid ML-1a cells with capsaicin blocked TNF-mediated activation of NF-κ-B in a dose- and time-dependent manner. Capsaicin treatment of cells also blocked the degradation of I-κ-B alpha, and thus the nuclear translocation of the p65 subunit of NF-κ-B, which is essential for NF-κ-B activation. TNF-dependent promoter activity of I-κ-B alpha, which contains NF-κ-B binding sites, was also inhibited by capsaicin.
Neurogenic inflammation has been successfully modeled using capsaicin. When injected intradermally, capsaicin evokes a temporary burning sensation lasting 3 to 5 minutes and a characteristic localized flare consisting of a red flush with slight edema (Holzer 1988). The capsaicin flare is thought to be induced by a local axon reflex involving release of neuropeptides such as SP and CGRP from sensory neurons (Holzer 1988). Additional mediators of the capsaicin flare are thought to include cytokines, prostaglandins, and other neuropeptides (Holzer 1991; Veronesi 1999). Within normal individuals, the size of the capsaicin flare over time is quite consistent (Jolliffe 1995).
The effect of glucocorticoids and catecholamines on the capsaicin-induced flare have been minimally examined. However, glucocorticoids have not been shown to block the capsaicin-induced flare (Ahluwalia 1994). Alpha adrenoreceptors are known to be involved in the pain response to capsaicin (Kinnman 1997).
Depending on the concentration used and the mode of application, capsaicin can selectively activate, desensitize, or exert a neurotoxic effect on small diameter sensory afferent nerves while leaving larger diameter afferents unaffected (Holzer, 1991; Winter et al., 1995). Sensory neuron activation occurs due to interaction with a ligand-gated nonselective cation channel termed the vanilloid receptor (VR-1) (Caterina et al., 1997), and receptor occupancy triggers Na+ and Ca2+ ion influx, action potential firing, and the consequent burning sensation associated with spicy food or capsaicin-induced pain. VR1 receptors are present on both C and Aδ fibers, and can be activated by capsaicin and its analogs, heat, acidification, and lipid metabolites (Tominaga et al., 1998; Caterina and Julius, 2001). Desensitization occurs with repeated administration of capsaicin, is a receptor-mediated process, and involves Ca2+- and calmodulin-dependent processes and phosphorylation of the cation channel (Winter et al., 1995; Wood and Docherty, 1997).
Capsaicin induces release of substance P and calcitonin gene-related peptide from both peripheral and central terminals of sensory neurons, and desensitization inhibits such release (Holzer, 1991); such inhibition may result from inhibition of voltage-gated Ca2+-currents (Docherty et al., 1991; Winter et al., 1995). Neurotoxicity is partially osmotic and partially due to Ca2+ entry with activation of Ca2+-sensitive proteases (Wood et al., 1989; Winter et al., 1995). In neonates, neurotoxicity can be lifelong (Janscó et al., 1977), whereas in adult animals receiving a localized dose, a reversible injury may occur as cell bodies capable of regeneration are left intact (Holzer, 1991). Both desensitization and neurotoxicity lead to analgesia in rodent paradigms, with specific characteristics of analgesia depending on the dose of capsaicin, route of administration, treatment paradigm (i.e., acute or repeated administration), and age of the animal (Holzer, 1991; Winter et al., 1995). The topical skin application of capsaicin to rodents produces analgesia (Kenins, 1982; Lynn et al., 1992), but variability in outcome can occur due to the concentration, the number of applications, and the different vehicles used that can affect the rate and extent of skin penetration (Carter and Francis, 1991; McMahon et al., 1991).
The distribution and metabolism of capsaicin and/or dihydrocapsaicin has been studied in rats. Capsaicin is distributed to the brain, spinal cord, liver and blood within 20 mins. of i.v. administration. Oral doses of dihydrocapsaicin in the rat showed metabolic activity associated with its absorption into the portal vein. Capsaicin and dihydrocapsaicin are metabolized in the liver by the mixed-function oxidation system (cytochrome P-450-dependent system). It is assumed that capsaicin is excreted in urine. In rats, most of dihydrocapsaicin is known to be rapidly metabolized and excreted in the urine (Rumsfield and West, 1991).
Acute intradermal injection of capsaicin to the skin in humans produces a burning sensation and flare response; the area of application becomes insensitive to mechanical and thermal stimulation, the area of flare exhibits a primary hyperalgesia to mechanical and thermal stimuli, and an area beyond the flare exhibits secondary allodynia (Simone et al., 1989; LaMotte et al., 1991). Repeated application to normal skin produces desensitization to this response and thus forms the basis of the therapeutic use of topical capsaicin in humans. Desensitization involves both physiological changes in the terminals of the sensory neuron noted above, as well as a degree of loss of sensory fiber terminals within the epidermis (Simone et al., 1989; Nolano et al., 1999). With respect to topical applications of capsaicin, it has been estimated that assuming 100% of a topically-applied dose is absorbed into the body, an application of 90 g capsaicin (2 tubes of cream, 0.025% capsaicin) per week would result in a daily exposure of 0.064 mg/kg capsaicin for a 50 kg person. This represents less than 10% of the dietary intake of a typical Indian or Thai diet (Rumsfield and West, 1991).
Topical capsaicin preparations of 0.025 and 0.075% are available for human use, and these produce analgesia in randomized double-blind placebo-controlled studies, open label trials, and clinical reports (Watson, 1994; Rains and Bryson, 1995). Capsaicin, is recognized by the U.S. FDA as a counterirritant for use in OTC topical analgesic drug products (Palevitch and Craker, 1995). It is used as a component in various counterirritant preparations (Leung and Foster, 1996), including ArthriCare® (Del Pharmaceuticals, Inc.) arthritis pain relieving rub, which contains Capsicum oleoresin (0.025% capsaicin) in combination with menthol USP and Aloe vera gel (Arky et al., 1999). Capsicum ointments, such as Zostrix® cream (GenDerm Corp.), containing 0.025% or 0.075% capsaicin, are used topically to treat shingles (herpes zoster) and post-herpetic neuralgia (Bernstein et al., 1987; Der Marderosian, 1999; Palevitch and Craker, 1995).
Topical capsaicin produces benefit in post-herpetic neuralgia (Bernstein et al., 1989; Watson et al., 1993), diabetic neuropathy (Capsaicin Study Group, 1992), postmastectomy pain syndrome (Watson and Evans, 1992; Dini et al., 1993), oral neuropathic pain, trigeminal neuralgia, and temperomandibular joint disorders (Epstein and Marcoe, 1994; Hersh et al., 1994), cluster headache (following intranasal application; Marks et al., 1993), osteoarthritis (McCarthy and McCarthy, 1992), and dermatological and cutaneous conditions (Hautkappe et al., 1998). Whereas pain relief is widely observed in these studies, the degree of relief is usually modest, although some patients have a very good result. Topical capsaicin is generally not considered a satisfactory sole therapy for chronic pain conditions and is often considered an adjuvant to other approaches (Watson, 1994). No significant benefit was reported in chronic distal painful neuropathy (Low et al., 1995) or with human immunodeficiency virus-neuropathy (Paice et al., 2000).
Capsaicin produces marked alterations in the function of a defined subpopulation of unmyelinated sensory afferents, termed C-polimodal nociceptors. Following the initial period of intense burning or stinging pain accompanied by erythema, topical capsaicin application causes insensitivity to further irritation by a variety of noxious stimuli. Accordingly, topical preparations of capsaicin find use as a topical therapy for a variety of cutaneous disorders that involve pain and itching, such as post-herpetic neuralgia, diabetic neuropathy, pruritus, psoriasis, cluster headache, postmastectomy pain syndrome, rhinopathy, oral mucositis, cutaneous allergy, detrusor hyperreflexia, loin pain/hematuria syndrome, neck pain, amputation stump pain, reflex sympathetic dystrophy, pain due to skin tumor and arthritis (Hautkappe et al., 1998).
The most frequently encountered adverse effect with capsaicin is burning pain at the site of application, particularly in the first week of application. This can make it impossible to blind trials and can lead to dropout rates ranging from 33 to 67% (Watson et al., 1993; Paice et al., 2000). Another factor in compliance is the time delay before therapeutic effect is observed (at least a week, but sometimes several weeks). One approach toward minimizing adverse effects and accelerating the rate of analgesia has been to deliver a higher capsaicin concentration (5-10%) under regional anesthesia, and this produced sustained analgesia lasting 1 to 8 weeks in cases of complex regional pain syndrome and neuropathic pain (Robbins et al., 1998). When topical local anesthetics were applied with 1% topical capsaicin, no alteration in pain produced by the capsaicin was observed in healthy subjects (Fuchs et al., 1999) indicating that this co-treatment was not sufficient to block the pain induced by capsaicin.
Because of intense burning or stinging pain, many patients are not tolerated in the long-term treatment with topical capsaicin and, therefore, have to discontinue the treatment before appearance of analgesic effect of capsaicin through prolonged administration. It was reported that 26 out of 39 (66.7%) patients suffering from post-herpetic neuralgia were not tolerated with a 0.025% capsaicin preparation (Zostrix, Gen Derm, USA). With a 0.075% preparation (Zostrix-HP, Gen Derm, USA), 5 out of 16 (31.3%) and 45 out of 74 (60.8%) patients with post-herpetic neuralgia were not tolerated (Peikert et al., 1991; Watanabe et al., 1994; Bernstein et al., 1989 and Watson et al., 1993).
Various capsaicin compositions have been developed over the years, in particular, the psoriatic composition of U.S. Pat. No. 4,486,450, the nasal composition of U.S. Pat. No. 5,134,166, and the composition of U.S. Pat. No. 4,997,853, the anti-inflammatory composition of U.S. Pat. No. 5,560,910, the composition of U.S. Pat. No. 5,962,532, the composition for animals of U.S. Pat. No. 5,916,565, the stomach treatments of U.S. Pat. No. 5,889,041, the composition of U.S. Pat. No. 5,827,886, the patch with medication of U.S. Pat. No. 5,741,510, all of which are incorporated by reference herein.
U.S. Pat. No. 6,593,370 discloses a topical capsaicin preparation for the treatment of painful cutaneous disorders and neural dysfunction. The preparation contains a nonionic, amphoteric or cationic surfactant in an amount effective to eliminate or substantially ameliorate burning pain caused by capsaicin.
U.S. Pat. No. 6,573,302 discloses a cream comprising: a topical carrier wherein the topical carrier comprises a member selected from the group comprising lavender oil, myristal myristate, and other preservatives including, hypericum perforatum arnica montana capric acid; and 0.01 to 1.0 wt. % capsaicin; 2 to 10 wt. % an encapsulation agent selected from the group comprising colloidal oatmeal hydrogenated lecithin, dipotassium glycyrlhizinate and combinations thereof; esters of amino acid; a light scattering element having a particle size up to 100 nm.; and a histidine.
U.S. Pat. No. 6,348,501 discloses a lotion for treating the symptoms of arthritis using capsaicin and an analgesic, and a method for making.
U.S. Pat. No. 5,962,532 disclose methods and compositions for treating pain at a specific site with an effective concentration of capsaicin or analogues. The methods involve providing anesthesia to the site where the capsaicin or analogues thereof is to be administered, and then administering an effective concentration of capsaicin to the joint. The anesthesia can be provided directly to the site, or at remote site that causes anesthesia at the site where the capsaicin is to be administered. For example, epidural regional anesthesia can be provided to patients to which the capsaicin is to be administered at a site located from the waist down. By pretreating the site with the anesthetic, a significantly higher concentration of capsaicin can be used. Effective concentrations of capsaicin or analogues thereof range from between 0.01 and 10% by weight, preferably between 1 and 7.5% by weight, and more preferably, about 5% by weight. This provides for greater and more prolonged pain relief, for periods of time ranging from one week to several weeks. In some cases the pain relief may be more sustained because the disease that underlies the pain may improve due to a variety of factors including enhancement of physical therapy due to less pain in the soft tissues which may foster enhanced mobilization of soft tissues, tendons, and joints.
U.S. Pat. No. 5,910,512 disclose a water-based topical analgesic and method of application wherein the analgesic contains capsicum, capsicum oleoresin and/or capsaicin. This analgesic is applied to the skin to provide relief for rheumatoid arthritis, osteoarthritis, and the like.
U.S. Pat. No. 5,403,868 discloses novel capsaicin derivatives containing thio-urea, processes for the production thereof, pharmaceutical compositions containing them and use thereof as pharmaceuticals.
U.S. Pat. No. 5,178,879 discloses clear, water-washable, non-greasy gels useful for topical pain relief contain capsaicin, water, alcohol and a carboxypolymethylene emulsifier. A method of preparing the gels is also disclosed
U.S. Pat. No. 5,021,450 relates to a new class of compounds having a variable spectrum of activities for capsaicin-like responses, compositions thereof, processes for preparing the same, and uses thereof. Compounds were prepared by combining phorbol related diterpenses and homovanillac acid analogs via esterification at the exocyclic hydroxy group of the diterpene. Examples of these compounds include 20-homovanillyl-mezerein and 20-homovanillyl-12-deoxyphorbol-13-phenylacetate.
U.S. Pat. No. 4,997,853 discloses a method and composition for treating superficial pain syndromes which incorporates capsaicin in a therapeutically effective amount into a pharmaceutically acceptable carrier and adding to this composition a local anesthetic such as lidocaine or benzocaine. The composition containing the anesthetic is then applied to the site of the pain. A variation on the treatment includes initial treatment with the composition containing the local anesthetic until the patient has become desenstitized to the presence of capsaicin and subsequent treatment with a composition omitting the local anesthetic.
US application 20050019436 provides compositions and methods for relieving pain at a site in a human or animal in need thereof by administering at a discrete site in a human or animal in need thereof a dose of capsaicin in an amount effective to denervate a discrete site without eliciting an effect outside the discrete location, the dose of capsaicin ranging from 1 μg to 3000 μg.
US application 20040224037 claims a use of Capsaicin (8-methyl-n-vanillyl-6-nonenamide), its derivatives, vanilloids and capsicum extract, to combat and control HIV (humans immunodeficiency virus) and AIDS (acquired immunodeficiency syndrome). An evaluation of a capsicum sp consumption of a long term aids survivors group permitted a definition of more efficacious ways to administer the substance. capsaicin intravenous and by subcutaneous or intramuscular administration at low concentration implemented by using infuses, it inhibits HIV replication and stimulates the production and proliferation of lymphocytes and cells NK. Also it acts as desinfectant in macrophages, and has a power as anticancer and antioxidant agent. Moreover has the property to control and annihilate common opportunistic illnesses related to HIV due to its triple antibiotic characteristics.
US application 20040146590 provides methods and kits for the selective ablation of pain-sensing neurons. The methods comprise administration of a vanilloid receptor agonist to a ganglion in an amount that causes death of vanilloid receptor-bearing neurons. Accordingly, the present invention provides methods of controlling pain and inflammatory disorders that involve activation of vanilloid receptor-bearing neurons.
US application 20030133995 discloses a chemical composition for an ingestible capsaicin neutralizer to neutralize the effect of capsaicin on the oral cavity, tongue, and esophagus when capsaicin from hot peppers is ingested by a user comprised of an effective neutralizing amount of casein protein, or the salt thereof, an alkali earth metal halide, and the balance water.
US application 20030082249 discloses a composition for use in treating or preventing mucositis, and/or xerostomia, including capsaicin or capsaicin derivative, and one or more additional compounds useful in treating mucositis and/or xerostomia, wherein the composition is provided in an oral delivery vehicle. The term capsaicin derivative and capsaicinoid as used in the disclosure are interchangeable and generally refer to capsaicin analogs. Among the capsaicinoids useful in the practice of the disclosure are capsaicin, the N-phenylmethylalkenamide capsaicin derivatives; dihydrocapsaicin; norhydrocapsaicin; nordihydrocapsaicin; homocapsaicin; homohydrocapsaicin; homodihydrocapsaicin; civamide (cis-capsaicin); nonivamide; NE-19550 (N-[4-hydroxy-3-methoxyphenyl)methyl]-9Z-octadecanamide) (olvanil); NE-21610 (N-[(4-(2aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octadecanamide) Sandoz Pharmaceutical Corp, East Hanover, N.J.); NE-28345 (N-(9Z-octadecenyl)-3-methoxy-4-hydroxyphenylacetamide; also known as N-oleyl-homovanillamide); and their analogs and derivatives (U.S. Pat. No. 5,762,963, which is incorporated herein by reference). NE-19550, NE-21610, and NE-28345 are discussed in Dray et al. (1990).
US application 20020058048 discloses a topical capsaicin preparation for the treatment of painful cutaneous disorders and neural dysfunction is disclosed. The preparation contains a nonionic, amphoteric or cationic surfactant in an amount effective to eliminate or substantially ameliorate burning pain caused by capsaicin.
US application 20010002406 discloses transdermal application of capsaicin (or a capsaicin analog) in a concentration from greater than about 5% to about 10% by weight to be an extremely effective therapy for treating neuropathic pain, so long as an anesthetic, preferably by means of a transdermal patch, is administered initially to the affected area to minimize the expected side effects from subsequent capsaicin application. Analogs of capsaicin with physiological properties similar to capsaicin are known (Ton 1955). For example, resiniferatoxin is described as a capsaicin analog by Blumberg, U.S. Pat. No. 5,290,816. U.S. Pat. No. 4,812,446, describes capsaicin analogs and methods for their preparation.
U.S. Pat. Nos. 4,493,848 and 4,564,633 disclose the derivatives of capsaicin, including short chain ester derivatives (C1-C6) of capsaicin for analgesia in human.
Cetyl myristoleate (CMO) is the common name for cis-9-cetyl myristoleate and the structure of cetyl myristoleate is shown in FIG. 3. In 1972 Diehl (1994) discovered that Swiss albino mice did not get arthritis after injection of Freund's adjuvant. Eventually, he was able to determine that cetyl myristoleate was the factor present naturally in mice which was responsible for this protection. When cetyl myristoleate was injected into various strains of rats, it offered the same protection against arthritis. Cetyl myristoleate is a natural medium chain fatty acid found in certain animals, including cows, whales, beavers, and mice. It has been proposed that cetyl myristoleate acts as a joint “lubricant” and anti-inflammatory agent.
The rational for the use of cetyl myristoleate is that it may inhibit the production of inflammatory prostaglandins and leukotrienes. The process of inflammation involves the release of proinflammatory cytokines (e.g., interleukin 1β and tumor necrosis factor-α). Fatty acids, especially n-6 fatty acids, have been proposed to reduce chronic inflammation in patients with rheumatoid arthritis by reducing leukotriene B4 from stimulated neutrophils and of interleukin-1 monocytes (Kremer 2000; 1996). In addition, other suggested mechanisms for the anti-inflammatory response observed with fatty acid treatment are reduced expression and activity of proteoglycan degrading enzymes and cytokines, suppression of leukocyte function, changes in adhesion molecule expression and apoptosis triggering, and alterations in signal transduction and membrane fluidity (Kremer 2000; Curtis 2000 and Heraud 2000).
U.S. Pat. Nos. 5,569,676, 4,113,881 and 4,049,824 disclose the use of cetyl myristoleate in both osteoarthritis and rheumatoid arthritis and several scientific studies have documented the benefit of cetyl myristoleate in relieving pain based upon the animal studies and several case histories (Siemendi 1997; Cochran 1996; Elkins 1997 and Hesslink 2002). In a double-blind study, 106 individuals with various types of arthritis who had failed to respond to non-steroidal anti-inflammatory drugs received cetyl myristoleate (540 mg per day orally for 30 days), while 226 others received a placebo. These individuals also applied cetyl myristoleate or placebo topically, according to their perceived need. Some 63.5% of those receiving cetyl myristoleate improved, compared with only 143% of those receiving the placebo (Siemandi 1997 and Cochran 1996).
A need exists for a topical preparation which eliminates or substantially ameliorates initial stinging pain caused by capsaicin observed in the administration with anti-inflammatory properties thereby making the preparation tolerable in long-term administration.
The purpose of the present application is to disclose the unexpected discovery that esters of capsaicin have significantly less burning pain at the site of the application and the synergistic combination of the esters of capsaicin and esters of myristoleic acid are extremely effective in treating pain in humans. The present invention does not rely on topical anesthetics, such as lidocaine (Entry 5310, p. 786 Merck Index, Tenth Edition 1983) and benzocaine (ethyl aminobenzoate, Entry 3710, p. 546 Merck Index, Tenth Edition, 1983) into formulations containing capsaicin, and then applying such formulations for the initial period of treatment to eliminate the painful burning from the application of capsaicin, allowing the patient to continue therapy while being able to feel through the skin onto which the cream is applied.